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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
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  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
  • C07C211/45—Monoamines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C62/08—Saturated compounds containing ether groups, groups, groups, or groups
  • C07C62/10—Saturated compounds containing ether groups, groups, groups, or groups with a six-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C62/30—Unsaturated compounds
  • C07C62/34—Unsaturated compounds containing ether groups, groups, groups, or groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
  • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

• the disclosure relates to methods of preparing (4bS,5aR)-12-cyclohexyl-N—(N,N-dimethylsulfamoyl)-3-methoxy-5a-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-4b,5,5a,6-tetrahydrobenzo[3,4]cyclopropa[5,6]azepino[1,2-a]indole-9-carboxamide (Compound I, formula I), its salts, and intermediates in the preparation of this compound.
• the compound has activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.
• HCV hepatitis C virus
• Hepatitis C virus is a major human pathogen, infecting an estimated 170 million persons worldwide. Hepatitis C virus (HCV) is the most common bloodborne infection in the USA and worldwide and is the leading cause of liver transplantation (Eric Chak et. al. Liver International 2011, 1090-1101). A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.; Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).
• HCV NS5B inhibitors which bind to a site referred to in the art as Site 1, including Compound I, have been disclosed in U.S. Pat. No. 7,456,166 (issued Nov. 25, 2008; US patent publication 20070270405, published Nov. 22, 2007).
• One aspect of the invention is a method for preparing the compound
• Another aspect of this method further comprises the coupling of
• Another aspect of this method further comprises a method for the coupling of the compound
• Another aspect of this method further comprises the reduction of the compound
• Another aspect of this method further comprises the cyclopropanation and hydrolysis of the compound
• Another aspect of this invention is a method comprising the coupling of
• Another aspect of this invention is a method comprising the coupling of the compound
• Another aspect of this invention is a method comprising the reduction of the compound
• Another aspect of this invention is a method comprising the cyclopropanation and hydrolysis of the compound
• Another aspect of the invention is a method comprising the preparation of the compound
• Another aspect of the invention is a method comprising the preparation of the compound
• Another aspect of the invention is the compound
• Another aspect of the invention is compound
• Another aspect of the invention is the compound
• Another aspect of the invention is the compound
• Another aspect of the invention is the compound
• Another aspect of the invention is the compound
• Scheme 1 and 2 describe synthetic preparations for an indole intermediate.
• Scheme 3 describes a synthetic procedure for making (4bS,5aR)-12-cyclohexyl-N—(N,N-dimethylsulfamoyl)-3-methoxy-5a-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-4b,5,5a,6-tetrahydrobenzo[3,4]cyclopropa[5,6]azepino[1,2-a]indole-9-carboxamide.
• the mixture was heated to 40° C., held until reaction completion was achieved, and distilled to 5-6 L/kg under vacuum (100-200 Torr) with a jacket temperature of 30-60° C. and a batch temperature of 30-45° C.
• Isopropanol (4 L/kg) was charged followed by 10 N sodium hydroxide (3.10 L, 31.0 mol, 5.00 equiv).
• the mixture was heated to 75 ⁇ 5° C., held until reaction completion was achieved and cooled to 20-22° C.
• 3N hydrochloric acid ( ⁇ 18 L/kg) was charged dropwise keeping the temperature ⁇ 30° C. until pH 1-2 was achieved.
• the mixture was warmed to 35° C., held for 1 h, and cooled to 5-20° C.
• N—(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide 1.5 g
• dichloromethane 4.50 mL
• cyclohexanone 1.17 mL
• triethylsilane 2.70 mL
• the mixture was cooled to 5° C. and trifluoroacetic acid (1.27 mL) was charged keeping the temperature below 20° C.
• the mixture was stirred at 20° C. for 3 h and filtered.
• the solids were washed with heptane (2 ⁇ 10 mL) and the solid dried in a vacuum oven at 50° C. for 2 days to obtain a 69.4% yield.
• N—(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (1.00 kg, 3.74 mol, 1.00 equiv)
• toluene (3.00 L/kg, 2.61 kg/kg)
• cyclohexanone 0.734 kg, 7.48 mol, 2.00 equiv
• triethylsilane (1.30 kg, 11.2 mol, 3.00 equiv).
• the mixture was aged for 0.5 h at 18-22° C. and trifluoroacetic acid (1.29 kg, 11.2 mol, 3.00 equiv) was charged to the reactor over 20-30 minutes.
• the mixture was heated to 45° C., held until reaction completion was achieved and cyclohexane (3.00 L/kg, 2.35 kg/kg) was charged.
• the mixture was cooled to 10-20° C., held for 2 h, and the slurry filtered.
• the reactor and cake were rinsed with cyclohexane (1.0 L/kg, 0.78 kg/kg).
• the wet cake was transferred to a reactor, methanol (4.00 L/kg, 3.16 kg/kg) was charged, the mixture was heated to 45-50° C. and held for 30 minutes. Water (4.0 kg/kg) was charged at 45-50° C. and the mixture was cooled to 20-25° C.
• the ligand (DPEphos, 0.5 umol) was loaded into a vial and 50 uL of a 0.01 M solution of Pd(OAc) 2 (0.5 umol) was charged. The mixture was shaken for 0.5 h at 20° C. To the vial was charged 50 uL of a 0.2 M solution of 6-bromo-3-cyclohexyl-1H-indole (1.0 equiv, 10 umol) and 50 uL of a 0.6 M solution of N,N-dimethylsulfamide (3.0 equiv, 30 umol). The vial was concentrated to dryness and K 2 CO 3 (3.0 equiv, 4.1 mg) was charged. The vial was equipped with a stirbar and 100 uL of toluene was charged. The vial was heated at 80° C. under 40 psi CO for 20 h. The vial was analyzed by HPLC for conversion.
• the compound was made according to a literature method (Tetrahedron 1999, 10120). The following optional recrystallization was developed. To a 1 L round-bottom flask equipped with overhead stirring, reflux condenser and thermocouple was charged 2-bromo-5-methoxybenzaldehyde (50.0 g) and 250 mL 2-propanol. The slurry was warmed to 45° C. to give a clear, faint yellow solution. Water (250 mL) was then added via addition funnel over the course of 10 minutes while maintaining the internal temperature above 42° C. Note: A slurry forms upon addition of the first approximately 1 ⁇ 3 of the water charge.
• Trimethylsulfoxonium iodide (1.2 kg) and potassium carbonate (1.6 kg) was charged and the mixture was heated to 55° C. until reaction completion was achieved. The mixture was cooled to 25° C. and filtered to afford product-rich filtrate.
• DMSO solution was added an aqueous 2.4 N solution of lithium hydroxide containing 0.23 kg lithium hydroxide. The mixture was held at 10° C. until reaction completion was achieved.
• water 5 L
• the biphasic mixture was separated and the product-rich aqueous layer was neutralized with concentrated hydrochloric acid until a pH of 4.0 was obtained. The product was crystallized. The slurry was filtered and the cake was washed with water.
• the toluene layer was washed with water (1.2 L).
• the toluene layer was distilled at 105 torr to reduce volume to 1.5 L.
• DABCO was charged as a solid into the reaction mixture (123 g, 1.10 mol), stirred to dissolve, and the reaction was cooled to ⁇ 5° C.
• TsCl (152 g, 0.80 mol) in toluene (1.1 L) was charged at ⁇ 5° C. to 5° C.
• the mixture was warmed to 20° C. and stirred for 1 h, followed by the addition of half brine (2.4 L).
• the mixture was held at 20° C. for 2 h and after a phase split the organic phase was washed with 2.4 L half brine solution.
• the mixture was cooled to 40° C. and 1.5 g of seeds were charged.
• the slurry was held at 40° C. for 30 min and 2.7 L heptane was charged at 40° C.
• the slurry was cooled to 20° C., held overnight and filtered.
• the cake was washed with 600 mL IPA:heptane (1:1) followed by 2 ⁇ 600 mL of heptanes.
• Wet cake was 413 g.
• a 10 g sample of wet cake was removed and the remaining cake was dried under vacuum at 40° C. for 16 h obtaining 346 g of product (74%), 99.2 HPLC area percent purity.
• the mixture was warmed to 20° C., stirred for 1 h and 5 wt % aqueous KCl. Additional toluene (2.4 L) was charged. After stirring at 40° C. for 2 h the phases were split. The toluene layer was washed with 5 wt % aqueous KCl (2.4 L) and the phases split at 40° C. The toluene layer was washed with water (1.2 L) and the phases split at 40° C.
• the batch was seeded with sodium (1-(((1R,2R)-2-(2-bromo-5-methoxyphenyl)-1-carboxylatocyclopropyl)methyl)-3-cyclohexyl-1H-indole-6-carbonyl)(N,N-dimethylsulfamoyl)amide (1.5 g) followed by THF (210 mL).
• THF 210 mL
• the slurry was held for 0.5 h at 60° C.
• Additional 10 N NaOH (45.5 mL, 0.46 mol) was charged over 0.5 h followed by THF (75 mL).
• IPA (0.90 L) was charged over 15 minutes.
• the slurry was held at 60° C. for 0.5 h, cooled to 20° C.
• the mixture was heated to reflux at 125-127° C. for 3-5 h and then cooled to 25° C. and water (60 mL) was added.
• KOH (3.0 g, purity 85%, 3 eq) was charged and the mixture stirred at 35-40° C. for 1 h.
• the reaction mixture was filtered on a Celite Pad and the phases were split discarding the toluene layer.
• MTBE 100 mL
• the mixture was acidified with 37% HCl to a pH of 2-3.
• the phases were split and the aqueous layer was extracted with MTBE (50 mL).
• the MTBE layers were combined and distilled at atmosphere pressure until the pot temperature increased to 70° C.
• the mixture was heated to 110° C. until reaction completion was achieved.
• the mixture was cooled to 25° C. and water (90 mL) was added.
• Aqueous potassium hydroxide (45 wt %, 2.76 g) was charged, the mixture was stirred at 25° C. for 1 h, after which 70 mL of methyl tert-butyl ether (MTBE) was added.
• MTBE methyl tert-butyl ether
• the biphasic reaction mixture was filtered through a plug of celite and the phases were split discarding the MTBE layer.
• To the aqueous rich layer was charged MTBE (110 mL), 200 proof absolute ethanol (30 mL) and 37 wt % HCl (8.60 g). The phases were split.
• the MTBE rich layer was washed two times with water (50 mL). DMAc (9 mL) was charged and the mixture was concentrated by distilling at atmosphere pressure until the pot temperature increased to >70° C. When the distillation was complete, the temperature was reduced to 50° C. and EtOH (70 mL) was added. At 50° C., 24 wt percent potassium ethoxide in ethanol solution (5.18 g) was charged over 2 h. After the addition, the slurry was cooled to 25° C. over 1 h and aged at 25° C. for 2 h. The solid was filtered and washed consecutively with EtOH (40 mL) and MTBE (40 mL). The product was dried at 65° C.
• the temperature of the reaction mixture was adjusted to 20° C., and then N,N-diisopropylethylamine (657.5 g, 5.09 mol, 3.0 equiv) was introduced to the mixture while maintaining the internal temperature ⁇ 27.5° C.
• the base charge was chased with an additional aliquot of acetonitrile (1 L), and the resulting mixture was aged at room temperature for 12 h.
• 2.5% starting material remaining) isopropyl acetate (10 L) was introduced, followed by saturated ammonium chloride solution (5 L, 5 vol), glacial acetic acid (575 g, 8.45 mol, 5.0 equiv) and water (5 L, 5 vol). The resulting mixture was agitated at 20-25° C.
• the organic layer was then treated with a solution of pH 7 KH 2 PO 4 /K 2 HPO 4 buffer solution (12.5 L, 12.5 vol), the mixture was agitated at 20° C. ⁇ T ⁇ 25° C. for 15 min, then left to settle for 15 min, and the resulting aqueous layer was discharged.
• the organic layer was then treated with a second portion of pH 7KH 2 PO 4 /K 2 HPO 4 buffer solution (12.5 L, 12.5 vol), the mixture was agitated at 20-25° C. for 15 min, then left to settle for 15 min, and the resulting aqueous layer was discharged.
• the product-rich organic layer was treated with a mixture of brine (5 L, 5 vol) and water (5 L, 5 vol). The resulting mixture was agitated at 20-25° C. for 15 min, then left to settle for 15 min, and the aqueous layer was discharged.
• the organic solution was then concentrated to approx. 7.5 L (100-300 mbar, T ⁇ 50° C.), and subsequently subjected to constant volume distillation, in order to reduce the water content to ⁇ 1000 ppm (IPC, KF). Absolute ethanol was charged (7.5 L), and constant volume distillation was continued (100-300 mbar, T ⁇ 50° C.) until the IPAc level was reduced to ⁇ 1% (as determined by GC).
• the reaction temperature was adjusted to 30-35° C., and the solution was subjected to polish filtration.
• the clarified solution was further concentrated (100-300 mbar, T ⁇ 50° C.) to a final volume of 10 L (10 volumes).
• the batch temperature was adjusted to 20° C., and ethanolic HCl (970 g of a 1.2 M solution, 1.2 equiv) was introduced, followed by (4bS,5aR)-12-cyclohexyl-N—(N,N-dimethylsulfamoyl)-3-methoxy-5a-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-4b,5,5a,6-tetrahydrobenzo[3,4]cyclopropa[5,6]azepino[1,2-a]indole-9-carboxamide hydrochloride seeds (10 g).
• the organic layer was then treated with a second portion of pH 7 KH 2 PO 4 /K 2 HPO 4 1 M buffer solution (250 mL, 12.5 L/kg), the mixture was agitated at 20-25° C. for 0.5 h, then left to settle for 15 min, and the resulting aqueous layer was discharged.
• the product-rich organic layer was treated with a mixture of saturated sodium chloride (100 mL, 5 L/kg) and water (100 mL, 5 L/kg). The resulting mixture was agitated at 20-25° C. for 0.5 h, then left to settle for 15 min, and the aqueous layer was discharged.
• the organic solution was then concentrated to approximately 7.5 L/kg at ⁇ 100 mbar, 20-25° C. and subsequently subjected to constant volume distillation by adding isopropyl acetate (300 mL, 15 L/kg), in order to reduce the water content to ⁇ 1000 ppm.
• the stream was diluted with isopropyl acetate (60 mL, 3 L/kg) and subjected to polish filtration, and the filter train was rinsed with isopropyl acetate (60 mL, 3 L/kg).
• the resulting stream was transferred to a clean, glass-lined 1-L reactor, concentrated to approximately 10 L/kg at 100 mbar, 20-30° C., and subjected to constant volume distillation by adding absolute ethanol (770 mL, 38.5 L/kg) at 100 mbar, 20-30° C., until the IPAc level was reduced to ⁇ 1 volume percent.
• methyl tert-butyl ether (MTBE) (466 mL, 23.3 L/kg) was added over 14 h by addition pump.
• MTBE methyl tert-butyl ether
• the resulting slurry was aged at 40-45° C. for 2 h, then cooled to 20° C. over 2 h.
• the slurry was discharged to a filter and the derived wet cake was washed with 2:1 MTBE:EtOH (1 ⁇ 80 mL, 4 L/kg) and MTBE (1 ⁇ 80 mL, 4 L/kg).
• the material was dried in a vacuum oven at 50° C.

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